microRNA Control of Dilated Cardiomyopathy Dilated cardiomyopathy is a major cause of heart failure and approximately 20-35% of cases have genetic etiologies. The link between the genetics and disease progression remains poorly understood, despite being a major focus of current research. microRNAs have emerged as important regulators of heart disease. Approximately 2000 of these short, non-coding RNA molecules function in vivo by repressing the stability and translation of protein-coding mRNAs. miRNAs regulate nearly all biological processes examined, often by suppressing multiple points in a pathway produce a coherent biological response to stimuli. We have recently used functional screening of whole genome collections of synthetic miRNAs to identify miRNAs that suppress cardiomyocyte contractility in vitro and shown that blocking one of these, miR-25, improves heart function in a heart failure model (Nature, 2014, doi:10.1038). We applied high throughput screening to identify miRNAs that regulate the decline in cardiomyocyte function in familial DCM using patient-specific hiPSCs. Mechanical strain and chronic adrenergic stimulation induce a number of these miRNAs. Together our data have revealed that miRNAs connect physiological stress to suppression of proteins that maintain calcium regulation and sarcomeric integrity. Here we propose to systematically investigate miRNA control of familial DCM. AIMS 1 and 2 will identify miRNAs that have the potential to suppress contractility in DCM, using patient hiPSC-cardiomyocytes (cTn-T R173W and R141W) and a mouse DCM model corresponding to one of the DCM patient hiPSC models (cTn-T R173W); AIM 3 will determine the proteins that are repressed by the miRNAs to influence disease, and AIM 4 will establish how miRNAs midiate the response to pathological stimuli of increased wall tension and chronic adrenergic stimulation that contribute to disease progression. In summary, the research addresses the hypothesis that familial DCM involves dysregulation of miRNAs that impair Ca2+ handling, contractility and sarcomere integrity. Elucidating the miRNAs and their protein targets should provide insight into disease progression and point to novel therapeutic targets.